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Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations

Active Publication Date: 2018-05-03
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for treating vascular malformations in humans by administering an agent that inhibits phosphoinositide 3-kinase (PI3K). This treatment approach is based on the discovery that activating mutations of PIK3CA are associated with the development of vascular malformations in humans and in an animal model. The patent also suggests using a combination of two PI3K inhibitors that work together to effectively treat the vascular malformation.

Problems solved by technology

Vascular malformations are clinically challenging because current classifications only take into account the patient outcome and the histological characterization.
Venous malformations are of great interest due to current lack of treatment and prognosis.
Moreover, pathogenesis of these lesions remain obscure.

Method used

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  • Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations
  • Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations
  • Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations

Examples

Experimental program
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example 2

7. SOMATIC PIK3CA MUTATIONS AS A DRIVER OF SPORADIC VENOUS MALFORMATIONS

[0132]7.1 Materials and Methods

[0133]Study Design.

[0134]This study was designed to confirm the effect of PIK3CA H1047R expression in the genesis of vascular malformations (VM). The prevalence of PIK3CA mutations in human specimens of VM were characterized using targeted next-generation sequencing. The cohort of patients was obtained from Memorial Sloan-Kettering Cancer Center (US) and from the Hospital de la Santa Creu i Sant Pau (Spain) and were reviewed by a board-certified pathologist (C.R.A). All patients provided informed consent. The findings were further confirmed using different mouse models that drive the expression of the PIK3CA transgene in a ubiquitous-dependent manner. For these experiments, cohorts of n=45 mice were used. Littermates were used as a control. Disease-free survival plots were analyzed using the Mantel-Cox Log-rank test. For efficacy studies with different inhibitors, animals were ran...

example 3

8. SOMATIC PIK3CA MUTATIONS AS A DRIVER OF SPORADIC VENOUS MALFORMATIONS

[0242]8.1 Summary

[0243]The present example shows that activating PIK3CA mutations give rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, mutations in PIK3CA and related genes of the PI3K / AKT pathway were identified in approximately 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. VM in mouse models was successfully treated using pharmacological inhibitors of PI3Kα administered either systemically or topically.

[0244]8.2 Results

[0245]PIK3CASprr2f-Cre Mice Develop Spinal and Cutaneous VM

[0246]To investigate the role of PIK3CA, the gene encoding the catalytic p110α subunit of PI3K (PI3Kα), oncogenicity in uterine cancer, the mouse strain LoxP-STOP-LoxP (LSL)-PIK3CAH1047R was used, which allows the expression of the activating PIK...

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Abstract

The present disclosure relates to methods of treating a vascular malformation in a subject expressing a gain-of-function mutation in a PIK3CA gene comprising administering, to the subject, an effective amount of an agent that inhibits phosphoinositide 3-kinase (“PI3K”).

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of International Patent Application No. PCT / US16 / 32779 filed May 16, 2016, which claims priority to U.S. Provisional Application No. 62 / 162,534 filed May 15, 2015; U.S. Provisional Application No. 62 / 265,641 filed Dec. 10, 2015; and U.S. Provisional Application No. 62 / 313,476 filed Mar. 25, 2016, priority to each of which is claimed, and the contents of each of which are incorporated by reference in their entireties.SEQUENCE LISTING[0002]The specification further incorporates by reference the Sequence Listing submitted herewith via EFS on Nov. 14, 2017. Pursuant to 37 C.F.R. § 1.52(e)(5), the Sequence Listing text file, identified as 0727340637SEQ.txt, is 16,048 bytes and was created on Nov. 14, 2017. The entire contents of the Sequence Listing are hereby incorporated by reference. The Sequence Listing does not extend beyond the scope of the specification and thus does not contain new matter.1. INTRODUCT...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61P9/00A61K31/4439A61K31/427A61K31/519A61K31/444
CPCA61K31/5377A61P9/00A61K31/4439A61K31/427A61K31/519A61K31/444A61K31/4375
Inventor BASELGA, EULALIACASTEL, PAUBASELGA, JOSE T.
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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